Evaluation of Drug-Drug Interaction Potential Between the Oral Antibiotic Zoliflodacin and the CYP3A4 Inhibitor Itraconazole: A Phase 1 Study in Healthy Participants.

Zoliflodacin is a first-in-class oral spiropyrimidinetrione antibiotic being developed for patients with uncomplicated gonorrhea, including those infected with multidrug-resistant strains. Because zoliflodacin is metabolized by cytochrome P450 3A4 (CYP3A4), concomitant administration with a CYP3A inhibitor has the potential to increase zoliflodacin plasma exposure. The aim of this phase 1 drug-drug interaction (DDI) study was to assess the effect of the strong CYP3A4 inhibitor itraconazole on the pharmacokinetics (PK) and safety of a 3 g single oral dose of zoliflodacin. This was an open label, 2-period, 2-treatment, fixed sequence crossover DDI study. Eighteen eligible adult participants were dosed and completed the study. When zoliflodacin was co-administered with itraconazole at steady state, as determined by itraconazole trough plasma concentrations, zoliflodacin exposure increased as measured by peak concentration (Cmax) by 1.03-fold and by area under the plasma-concentration time curve (AUC) from time 0 to last measurable plasma concentration (AUC0-last) and from time 0 extrapolated to infinity (AUC0-∞) by 1.39- and 1.38-fold, respectively. Eight participants (44.4%) had a total of 15 mild treatment-emergent adverse events (TEAEs), with three considered related to treatment. There were no deaths or serious TEAEs and no participant withdrew. No clinically significant abnormal laboratory values, vital signs, or electrocardiogram findings were reported. In conclusion, the Cmax of zoliflodacin was essentially unchanged (1.03-fold higher) when co-administered with a strong CYP3A4 inhibitor, while AUC exposures increased by less than 1.5-fold, which, combined with an acceptable safety profile, indicate a low DDI potential between zoliflodacin and CYP3A4 inhibitors.